SRC2 controls CD4+ T cell activation via stimulating c-Myc-mediated up-regulation of amino acid transporter Slc7a5
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ABSTRACT:
PROVIDER: PRJNA955196 | ENA |
REPOSITORIES: ENA
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Project description:The effects of loss of the large neutral amino acid transporter Slc7a5 (aka Lat1) on mouse embryonic development were investigated. Slc7a5 fl/fl mice harbouring two copies of the Slc7a5 targeted allele (exon 1 of Slc7a5 flanked with two loxP sites), were crossed with a mouse line ubiquitously expressing cre recombinase under the Bal1 promoter (Bal1-cre) to obtain a global Slc7a5 knockout mouse (Poncet et al. 2014 PLoS One 9: e89547). Heterozygous Slc7a5+/- C57Bl/6 mice were viable and fertile and were bred free of Bal1-cre in subsequent generations. Slc7a5 -/- embryos were obtained by inter-crossing heterozygotes and a phenotype was apparent by E9.5. To identify the first cellular processes affected by Slc7a5 loss RNAseq was carried out to compare transcriptomes of null and wildtype E8.5 embryos.
2019-06-01 | E-MTAB-6336 | biostudies-arrayexpress
Project description:Oncogenic KRAS mutations and inactivation of the APC tumour suppressor co-occur in colorectal cancer (CRC). Despite efforts to target mutant KRAS directly, most therapeutic approaches focus upon downstream pathways, albeit with limited efficacy. Moreover, mutant KRAS alters the basal metabolism of cancer cells, rendering them ‘addicted’ to glutamine supporting proliferation. We show that concomitant mutation of Apc and Kras in the mouse intestinal epithelium profoundly rewires metabolism, increasing glutamine consumption. Furthermore, SLC7A5, a glutamine antiporter, is critical for colorectal tumorigenesis in models of both early and late-stage metastatic disease. Mechanistically, SLC7A5 maintains intracellular amino-acid levels following KRAS activation through transcriptional and metabolic reprogramming. This supports the increased demand for bulk protein synthesis that underpins enhanced proliferation of KRAS-mutant cells. Moreover, targeting protein synthesis, via mTORC1 inhibition, cooperates with Slc7a5 deletion to abrogate growth of established KRAS-mutant tumours. Together, these data suggest SLC7A5 as an attractive target for therapy-resistant KRAS-mutant CRC.
2020-11-11 | GSE160479 | GEO
Project description:The amino acid transporter SLC7A5 is required for efficient growth of KRAS-mutant colorectal cancer
| PRJNA673351 | ENA
Project description:The intestine is the critical organ not only for processing and resorbing nutrients from ingested food but also for defending the organism from external stresses such as pathogens. These functions are mainly carried out by the epithelium which is constantly being self-renewed throughout adult life. Intestinal epithelial homeostasis is maintained through well-controlled cell proliferation of the stem cells and transient amplifying cells and the apoptotic degeneration of epithelial cells, mostly at or near the tip of the villi. Many genes and pathways have been found to influence intestinal epithelial cell proliferation. Among them is the mTORC1 signaling pathway, whose activation is known to increase cell proliferation. Here, we report the first intestinal epithelial specific knockout (IEC-KO) of an amino acid transporter capable of activating mTORC1. We show that the transporter, slc7a5, is highly expressed in the intestinal crypt and slc7a5 IEC-KO leads to expected reduction in mTORC1 signal in the crypt or even in intestinal organoids in vitro. Surprisingly, slc7a5 IEC-KO leads to increased proliferation of both transit amplifying cells and crypt base stem cells but a reduction in the secretory cells, particularly mature Paneth cells in the crypt base. Our scRNA-seq and electron microscopic analyses reveals that slc7a5 IEC-KO causes dedifferentiation of the Paneth cells, leading to drastically reduced secretory granules and lysozyme expression without affecting the overall Paneth cell number. We further show that slc7a5 IEC-KO mice are prone to induced colitis due to this loss of Paneth cell differentiation. We propose a model where slc7a5 regulates secretory cell differentiation to affect stem cell niche and/or inflammatory response to regulate cell proliferation in the crypts.
2024-04-24 | GSE216930 | GEO
Project description:Purpose: Since SRC2 is a transcriptional co-activator that is believed to regulate cellular function by controlling gene expression, RNA-seq analysis was performed to detect the transcriptome of SRC2fl/fl and SRC2fl/fl/CD4-Cre CD4+ cells 4 weeks post adoptive transferred to Rag1-/-
2023-05-01 | GSE229633 | GEO
Project description:Autism spectrum disorders (ASD) are a group of genetic disorders often overlapping with other neurological conditions. We previously described abnormalities in the branched chain amino acid (BCAA) catabolic pathway as a cause of ASD. Here we show that the solute carrier transporter 7a5 (SLC7A5), a large neutral amino acid transporter localized at the blood brain barrier (BBB), has an essential role in maintaining normal levels of brain BCAAs. In mice, deletion of Slc7a5 from the endothelial cells of the BBB leads to decreased levels of brain BCAAs, abnormal mRNA translation and severe neurological abnormalities. Furthermore, we identified several patients with autistic traits and motor delay carrying deleterious homozygous mutations in the SLC7A5 gene. Finally, we demonstrate that BCAA intracerebroventricular administration ameliorates abnormal behaviors in adult mutant mice. Our data elucidate a neurological syndrome defined by SLC7A5 mutations and support an essential role for the BCAA in human brain function.
2016-12-22 | GSE87808 | GEO
Project description:T cell clonal expansion and differentiation are critically dependent on the transcription factor c-Myc (Myc). Herein we use quantitative mass-spectrometry to reveal how Myc controls antigen receptor driven cell growth and proteome restructuring in CD4+ and CD8+ T cells. Quantitative proteomics was performed on naive wild-type (WT) and 24 hr T cell receptor (TCR) activated Myc WT and Myc-deficient T cells. Analysis of copy numbers per cell of >7000 proteins provides new understanding of the selective role of Myc in controlling the protein machinery that shapes T cell fate. The data identify both Myc dependent and independent metabolic processes in immune activated T cells. We uncover that a primary function of Myc is to induce amino acid transporter expression. Quantitative proteomics of 24 hr TCR activated Slc7a5 WT and Slc7a5-deficient CD4 T cells reveals that loss of a single Myc-controlled amino transporter, Slc7a5, can effectively phenocopy the impact of Myc deletion. This study thus provides a comprehensive map of how Myc selectively shapes T cell phenotypes and reveals that Myc induction of amino acid transport is pivotal for subsequent bioenergetic and biosynthetic programs.
2020-02-25 | PXD016105 | Pride
Project description:Glucagon supports glucose homeostasis by stimulating hepatic gluconeogenesis, in part by promoting the uptake and conversion of amino acids into gluconeogenic precursors. Genetic disruption or pharmacologic inhibition of glucagon signaling results in elevated plasma amino acids, and compensatory glucagon hypersecretion involving expansion of pancreatic α-cell mass. Regulation of pancreatic α- and β-cell growth has drawn a lot of attention because of potential therapeutic implications. Recent findings indicate that hyperaminoacidemia triggers pancreatic α-cell proliferation via an mTOR-dependent pathway. We confirm and extend these findings by demonstrating that glucagon pathway blockade selectively increases expression of the sodium-coupled neutral amino acid transporter Slc38a5 in a subset of highly proliferative α-cells, and that Slc38a5 is critical for the pancreatic response to glucagon pathway blockade; most notably, mice deficient in Slc38a5 exhibit markedly decreased α-cell hyperplasia to glucagon pathway blockade-induced hyperaminoacidemia. These results show that Slc38a5 is a key component of the feedback circuit between glucagon receptor signaling in the liver and amino acid-dependent regulation of pancreatic α-cell mass in mice.
2017-05-01 | GSE89636 | GEO
Project description:Surprisingly little is known about the critical metabolic changes that neural cells have to undergo during development and how even mild, temporary shifts in this program can influence brain circuitries and behavior. Inspired by the discovery that mutations in SLC7A5, a transporter of metabolically-essential large neutral amino acids (LNAAs), lead to autism, we employed metabolomic profiling to study the metabolic states of the cerebral cortex across different developmental stages. We found that the forebrain undergoes significant metabolic remodeling throughout development, with certain groups of metabolites showing stage-specific changes. But what are the consequences of interfering with this metabolic program? By manipulating Slc7a5 expression in neural cells, we found that the metabolism of LNAAs and lipids are interconnected in the cortex. Deletion of Slc7a5 in neurons perturbs specifically the postnatal metabolic state leading to a shift in lipid metabolism and a stage- and cell-type-specific alteration in neuronal activity patterns, resulting in a long-term circuit dysfunction.
2023-03-29 | GSE218713 | GEO
Project description:Oncogenic MYC selectively activates Slc7a5 and Slc43a1 transcription and thus promotes essential amino acids (EAAs) uptake in Daudi cells. Elevated EAAs in turn stimulate Myc mRNA translation, prompting us to investigate whether Slc7a5/Slc43a1 inhibition affects MYC-dependent transcription. We performed microarrays to profile global gene expression and to identify Slc7a5-regulated genes.
2019-11-11 | GSE106869 | GEO